1. Field of the Invention
The present invention relates generally to an improved valve apparatus for dispensing chemical reagents and other liquids and, specifically, to a reagent dispensing valve that is particularly adapted for dispensing precise microfluidic quantities of chemical reagents.
2. Background of the Related Art
Clinical testing of various bodily fluids conducted by medical personnel are well established tools for medical diagnosis and treatment of various diseases and medical conditions. Such tests have become increasingly sophisticated, as medical advancements have led to many new ways of diagnosing and treating diseases.
The routine use of clinical testing for early screening and diagnosis of diseases or medical conditions has given rise to a heightened interest in simplified procedures for such clinical testing that do not require a high degree of skill or which persons may conduct on themselves for the purpose of acquiring information on a physiological relevant condition. Such tests may be carried out with or without consultation with a health care professional. Contemporary procedures of this type include blood glucose tests, ovulation tests, blood cholesterol tests and tests for the presence of human chorionic gonadotropin in urine, the basis of modem home pregnancy tests.
One of the most frequently used devices in clinical chemistry is the test strip or dip stick. These devices are characterized by their low cost and simplicity of use. Essentially, the test strip is placed in contact with a sample of the body fluid to be tested. Various reagents incorporated on the test strip react with one or more analytes present in the sample to provide a detectable signal.
Most test strips are chromogenic whereby a predetermined soluble constituent of the sample interacts with a particular reagent either to form a uniquely colored compound, as a qualitative indication of the presence or absence of the constituent, or to form a colored compound of variable color intensity, as a quantitative indication of the amount of the constituent present. These signals may be measured or detected either visually or via a specially calibrated machine.
For example, test strips for determining the presence or concentration of leukocyte cells, esterase or protease in a urine sample utilize chromogenetic esters which produce an alcohol product as a result of hydrolysis by esterase or protease. The intact chromogenetic ester has a color different from the alcohol hydrolysis product. The color change generated by hydrolysis of the chromogenetic ester, therefore provides a method of detecting the presence or concentration of esterase or protease, which in turn, is correlated to the presence or concentration of leukocyte cells. The degree and intensity of the color transition is proportional to the amount of leukocyte esterase or HLE detected in the urine. See U.S. Pat. No. 5,464,739.
The emergence and acceptance of such diagnostic test strips as a component of clinical testing and health care in general has led to the development of a number of quality diagnostic test strip products. Moreover, the range and availability of such products is likely to increase substantially in the future.
Because test strips are used to provide both quantitative and qualitative measurements, it is extremely important to provide uniformity in distribution of the reagents on the test strip substrate. The chemistry is often quite sensitive and medical practice requires that the testing system be extremely accurate. When automated systems are used, it is particularly important to ensure that the test strips are reliable and that the measurements taken are quantitatively accurate.
Application of one or more reagents to a test strip substrate is a highly difficult task. The viscosities and other flow properties of the reagents, their reactiveness with the substrate or other reagents vary from reagent to reagent, and even from lot to lot of the same reagent. It is also sometimes necessary or desirable to provide precise patterns of reagent on the test strip having predetermined reagent concentrations. For example, some test strips provide multiple test areas that are serially arranged so that multiple tests may be performed using a single test strip. U.S. Pat. No. 5,183,742, for instance, discloses a test strip having multiple side-by-side detection regions or zones for simultaneously performing various tests upon a sample of body fluid. Such a test strip may be used to determine, for example, levels of glucose, protein, and the pH of a single blood sample.
Typically, a micro-droplet dispensing apparatus is utilized in the preparation and/or analysis of test strips. Of course, micro-droplet dispensing is not limited in application to test strip fabrication and analysis, but it also has a wide variety of other research and non-research related applications in the biodiagnostics, pharmaceutical, agrochemical and material sciences markets. For example, dispensing technology is used in genomic research and analysis, drug screening, live cell dispensing and ink jet printing among others.
Moreover, in addition to dispensing, some applications may also involve aspiration of a chemical reagent or other liquid, wherein a quantity of fluid is aspirated (xe2x80x9csuckedxe2x80x9d) from a source and then dispensed (xe2x80x9cspatxe2x80x9d) into or onto a target for further testing and/or processing. For example, a typical application would include a source composed of a 96-microwell plate with a transfer of reagent to a glass slide, microwell plate or membrane.
For several years the industry has been developing dispensing methods based on the use of solenoid valve dispensers. Solenoid valve dispensers generally comprise a small solenoid activated valve which can be opened and closed electronically at high speeds. Solenoid valves of this type are commercially available from sources such as The Lee Company of Westbrook, Conn. The solenoid valve is typically connected to a pressurized vessel or reservoir containing the fluid to be dispensed. In operation, the solenoid is energized by a pulse of electrical current, which opens the valve for a pre-determined duty-cycle or open time. This allows a small volume of liquid to be forced through the nozzle forming a droplet which is then ejected from the valve onto the target. The size and frequency of the droplets and the amount of reagent flow onto the target is typically controlled by adjusting the frequency and pulse-width of energizing current provided to the solenoid valve and/or by adjusting the pressure of the reservoir.
There are several major limitations associated with using a conventional solenoid valve, such as the Lee valve, as a drop-on-demand valve in a reagent dispensing system. The Lee valve generally comprises a solenoid actuator element and a valve element with these two elements being integrated to form a unitary component. The various components of the valve element present a tortuous path for the fluid to flow through. Such a tortuous fluid path results in significant disadvantages, such as localized pressure drops which undesirably lead to bubble precipitation of air or gas in solution. The entrapment of these bubbles in the fluid path can not only degrade the quality of the reagent or liquid dispensed but can also render the dispenser susceptible to clogging. Thus conventional dispensing valves require frequent purges of the fluid into a waste receptacle, thereby, disadvantageously, reducing process efficiency and increasing wasteful consumption of reagent. Moreover, the air or gas bubbles affect the compressibility of the fluid which can complicate the operational dynamics of the dispense and aspirate/dispense functions.
While some of these bubble generation problems can be controlled or mitigated by adding surfactants or various other chemical additives to modify the surface tension and/or other fluid and flow characteristics of the reagent, compatible chemistry is not available for all reagents. Also the use of surfactants and other chemicals can often lead to other problems in the dispensing apparatus, and its operation and application. Thus, there is a major reliability problem with many conventional solenoid valve dispensers that needs to be addressed.
Moreover, in most such valves as the Lee valve, the solenoid actuator is sealed inside the fluid containing housing. In many cases, the fluid is forced to flow in a passage between the solenoid actuator and the inner housing wall. This, undesirably, renders the fluid in the passage to be proximate to the electromagnetic coil of the solenoid actuator. Since the energizing of the solenoid coil can generate significant heat, the nearby fluid can experience substantial temperature rises. These temperature changes can further accentuate the bubble generation problem, and also lead to fluid degradation.
Additionally, the tortuous fluid path through conventional solenoid valves causes fluid mixing and entrapment of dead volumes of fluid. This dead volume entrapment can be particularly severe in the passage between the solenoid actuator and the inner housing wall. Undesirably, this fluid mixing and entrapment can lead to fluid degradation, contamination and dilution problems in dispense and aspirate/dispense operations, thereby, requiring additional fluid movements through the valve to flush out degraded fluid and/or contaminants.
Also, the unibody construction of typical actuator and valve elements limits the adaptability of the dispense system because the actuator is permanently incorporated with a particularly configured valve element and can only be used with that particularly configured valve element. Undesirably, this unibody construction complicates repair, maintenance and replacement of the valve and, hence, undesirably adds to the cost of the system.
Another problem associated with conventional solenoid valves is that many of the different materials that they are fabricated from are exposed to fluid and may be susceptible to chemical attack by some solvents. Disadvantageously, this can not only cause valve malfunction but can also lead to fluid contamination. Thus, it would be desirable to have a versatile valve which is fabricated from materials that are chemically inert to a wide variety of solvents.
Also, process efficiency can be greatly enhanced by running assays in high-density microplates, such as 384-well, 864-well, 1526-well and greater microplates, by providing dimensionally small valves. Assay miniaturization can be a very important and desirable aspect, for example, in high density applications such as genomic research, drug discovery and other applications. But, it is difficult using conventional construction methods to fabricate a typical solenoid dispenser having a diameter less than about 7 to 8 mm.
Moreover, in many applications more than one dispense or aspirate/dispense line is required to achieve high speed parallel processing. For example, 8-channels or 96-channels are commonly used in microtiter plate type applications to improve process throughput. In such situations valve costs per line can be very high which can preclude their use in high-density applications. Thus, it would be desirable to provide not only miniaturized valves but also valves that can be manufactured at a reasonably low cost.
Other desirable aspects of a valve for a dispensing system include a wide operating range, low power requirement, quick setup/priming, ease of hooking up and high operational safety.
A reagent dispensing valve constructed in accordance with one preferred embodiment of the present invention overcomes some or all of the aforementioned disadvantages by incorporating separate valve and actuator portions that substantially minimize localized fluid pressure drops and, desirably, minimizes fluid entrapment and mixing.
The valve portion, preferably, includes a plunger and a seat which are disposed in a valve cavity to define a valve orifice opening. The plunger and valve are configured to minimize the pressure drop through the valve orifice opening, thereby, advantageously, discouraging bubble formation. The plunger is adapted to seal against the seat to block the valve orifice opening when the valve is in the closed position. Preferably, the plunger is substantially blunt faced and the seat is substantially rounded. In other preferred embodiments of the present invention, the plunger may be substantially wedge faced or substantially spherically faced, though other plunger shapes may be used with efficacy, and the seat may be beveled or flat, though other seat shapes may be used with efficacy. Preferably, the plunger has a resilient exterior that can sealingly engage the seat. Preferably, the valve cavity is generally tapered in the direction of the seat, thereby, advantageously, discouraging bubble accumulation Preferably, the valve cavity is configured to optimally minimize its volume, and hence reduce the possibility of fluid entrapment sites or xe2x80x9cdead spotsxe2x80x9d forming in the valve cavity. Preferably, the fluid flows into the valve cavity through a concentric feed which desirably further discourages xe2x80x9cdead spotsxe2x80x9d of fluid to form in the valve cavity.
In one preferred embodiment of the present invention, the actuator is a solenoid actuator. The solenoid actuator is adapted to open and close the valve at a predetermined frequency and duty cycle by displacing the plunger. Preferably, the plunger is in mechanical communication with a movable core, which is spring biased in the direction of the seat, of the actuator. The actuator is substantially sealingly engaged with the valve portion via a resilient diaphragm which isolates the actuator from the fluid in the valve portion. Additionally, the fluid path through the valve is substantially decoupled from the solenoid actuator and the fluid enters the valve through a substantially cylindrical cavity in a fitting of the actuator, thereby, protecting the fluid from undesirable heating and other deleterious effects. In one preferred embodiment of the invention, the plunger is molded into the diaphragm. Preferably, the valve portion is removably attachable from the solenoid actuator. Desirably, this separation of function adds to the adaptability and modularity of the valve of the present invention.
In one preferred embodiment of the present invention, the valve includes an optional bubble trap. Preferably, the bubble trap is in fluid communication with the valve cavity via the concentric feed and the cylindrical cavity of the actuator fitting. The bubble trap is disposed adjacent to the cavity of the actuator fitting and also has a cavity which is spaced from and disposed generally above the valve cavity. Preferably, the bubble trap cavity is dimensioned to be substantially larger than the actuator fitting cavity. Advantageously, the positioning and dimensioning of the bubble trap cavity encourages gaseous bubbles that are formed in the valve to buoyantly rise into the bubble trap, thereby avoiding valve malfunction. Preferably, the bubble trap can purge the fluid containing bubbles into a sump.
The valve of the present invention in combination with a positive displacement pump, a fluid reservoir, a tip and a nozzle can dispense precise quantities of fluid and can aspirate a source fluid, while advantageously minimizing bubble formation and accumulation in the valve. The valve can be used to form droplets in the range from about 100 picoliters (pL) to about 10 nanoliters (nL) or more.
Those of ordinary skill in the art will readily recognize the versatility of the present invention and the benefits it presents over conventional prior art reagent dispensing valves. The construction of the valve permits desirable adaptability and minimizes undesirable gaseous bubble precipitation and accumulation within the fluid in the valve. In one preferred embodiment the valve also provides means to efficiently remove these bubbles from the valve.
Other specific provisions and advantages of the present invention will become apparent from a reading and study of the specification, claims and figures. As will be realized by those skilled in the art the invention is capable of modifications in various respects, all without departing from the scope and utility of the invention as disclosed herein. Accordingly the specification and figures should be regarded as illustrative in nature, and not as restrictive.